1. Technical Field
The present invention generally relates to the technical field of compounds and methods for the treatment or prophylaxis of sepsis and toxic shock. The present invention more specifically relates to the technical field of using a sophorolipids mixture and the administration of such a mixture for the treatment or prophylaxis of animals and humans for sepsis and septic shock.
2. Prior Art.
Septic shock and sepsis can be a life threatening systemic bacterial intoxication. Septic shock and sepsis can be associated with organ dysfunction, hypoperfusion, or hypotension. With early and intensive treatment including the use of antibiotics and intensive life support, the serious consequences of septic shock and sepsis can sometimes be avoided. However, despite the use of such treatments, the mortality rate remains high and in some cases can range from 25% to 75%.
Chills, fever, nausea, vomiting, diarrhea, and prostration characterize clinical symptoms of septic shock and sepsis. The subsequent development of septic shock is characterized by tachycardia, tachypnea, hypotension, peripheral cyanosis, mental obtundation, and oliguria. As septic shock and sepsis progresses, the clinical symptoms can include heart failure, respiratory insufficiency, and coma. Mortality often results from pulmonary edema, cardiac arrhythmia and failure, disseminated intravascular coagulation with bleeding, or cerebral anoxia.
The pathogenesis of septic shock and sepsis usually results from the systemic and unregulated host response to the bacterial antigens, which results in an elaborate and extensive array of chemical mediators. Specifically, the host's immune system is triggered by the lipopolysacchraride (LPS) from the outer membrane of gram-negative bacteria. The LPS over-stimulates the hosts' immune response by activating monocytes/macrophages, neutrophils, and endothelial cells. The activation of these cells results in an elaborate and extensive array of proinflammatory mediators, which can include cytokines, lipids, oxygen and nitrogen radical intermediates, complement, catecholamines, histamines, and others. The chemical mediators can cause local damage to cells and systemic toxic effects.
First described in 1961, sophorolipids occur as a mixture of macrolactone and free acid structures that are acetylated to various extents at the primary hydroxyl position of the sophorose ring. Gorin, P. A. et al., Can. J. Chem., vol. 39, p. 846 (1961). Careful examinations have revealed that at least eight structurally different sophorolipids are produced. Davila, A. M. et al., J. Chromatogr., vol. 648, p. 139 (1993). The main component of sophorolipids is 17-hydroxyoctadecanoic acid and its corresponding lactone. Tulloch, A. P. et al., Can. J. Chem., vol. 40, p. 1326 (1962) and Tulloch, A. P. et al., Can J. Chem., vol. 46, p. 3337 (1968).
Work has been carried out to tailor sophorolipid structure during in vivo formation, mainly by the selective feeding of different lipophilic substrates. Zhou, Q.-H., et al., J. Am. Oil Chem. Soc., vol. 72, p. 67 (1995). Also unsaturated C-18 fatty acids of oleic acid may be transferred unchanged into sophorolipids. Rau, U. et al., Biotechnol. Lett., vol. 18, p. 149 (1996). However, while physiological variables during fermentation have provided routes to the variation of sophorolipid composition, this has not led to well-defined pure compounds.
Existing data suggests that glycolipids may be useful in treating very severe immune disorders. For example, glycolipids have been reported to be of interest for in vivo cancer treatment/antitumor cell activity, treatment of autoimmune disorders, in vivo and in vitro antiendotoxic (septic) shock activity, regulation of angiogenesis, and apoptosis induction, all by cytokine activity. See, e.g., U.S. Pat. No. 5,597,573 to Massey, U.S. Pat. No. 5,514,661 to Piljac, U.S. Pat. No. 5,648,343 to Carlson, and the references cited in notes 9-13 of Bisht, K. S. et al., J. Org. Chem, vol. 64, pp. 780-789 (1999). However, it has not been shown that sophorolipids can achieve the same results.
Thus, it can be seen that there is need for improved and new compounds and methods for the prophylaxis and treatment of septic shock and sepsis. It is to this need that the present invention is directed.